While it is difficult to give an adequate description of inflammatory phenomena in terms of underlying cellular events in the injured tissue, there are certain features of the process that are generally agreed to be characteristic. These include fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema, oedema, tenderness and pain. During this complex response, chemical mediators such as histamine, serotonine, leukotrienes, prostaglandines, various chemotactic factors, bradykinin, lymphokines, kinin and complement system, lysosomal enzymes and cyclic nucleotides are liberated locally. Phagocytic cells migrate into the area, and cellular lysosomal membranes may be ruptured, releasing lytic enzymes. All these events contribute to the inflammatory response.
Several drugs are employed to suppress the manifestations of inflammation, including the adrenocorticosteroids, the large group comprising the so called non-steroid anti-inflammatory drugs or NSAIDs, and drugs such as immunosuppressive agents, chloroquine, penicillamine and gold salts.
NSAIDs are chemically a heterogeneous group of drugs, mainly constituting aromatic substituted carboxylic acids. Pharmacologically, they have anti-inflammatory, antipyretic and analgetic effects, and they inhibit prostaglandin synthesis and decrease thrombocyte aggregation. The mode of action of NSAIDs is not yet fully understood, although it is known that they inhibit one or more of the mediator substances of inflammation. However, there is no good correlation between inhibition of prostaglandin synthesis and anti-inflammatory effect. The main indication for NSAIDs is rheumatic diseases, particularly where inflammatory processes in supporting tissues give rise to pain and joint-stiffness. Furthermore, the analgetic effects can be used as symptomatic pain relief in cases where the prostaglandin inhibitory effect can be utilized, such as dysmennorrhoea, urolithiasis, etc. Some of the drugs, including indomethacin, have also been used topically on the skin in the treatment of various dermatoses and as a topical anti-inflammatory agent in the eye.
The use of NSAIDs gives rise to a broad spectrum of side effects. Severe and often fatal blood dyscrasias are often seen, notably following the use of phenylbutazone, and gastrointestinal side effects are common with phenylbutazone, salicylates and indomethacin. Allergic reactions are common and may in some cases be due to prostaglandin inhibition with a resulting secondary increase in leukotriene levels. Hepatotoxicity and nephrotoxicity as well as side effects of the central nervous system are also common with these drugs.
Adrenocorticosteroids, and especially glucocorticoids, have potent anti-inflammatory effects when used in pharmacological doses. They specifically inhibit the early vascular phase of the inflammatory process by decreasing the vascular permeability and thereby granulocyte migration. Glucocorticoids also interfere with late inflammatory and reparative processes, in that they inhibit the proliferation of mesenchymal cells and the production of intercellular macromolecules, including proteoglycanes and collagen. It has been shown experimentally that glucocorticoids inhibit, far example, macrophage function, production of humoral antibodies, cellular immunity, and possibly the release of lysosomal enzymes. The indications for systemic use of glucocorticoids are apart from substitution therapy very limited, because of side effects, and should be restricted to severe inflammatory rheumatic diseases, severe cases of allergic diseases such as asthma bronchiale and status asthmaticus and cases of haematological, renal, and gastrointestinal immunological diseases. Topical use involves a much lower risk of side effects, and glucocorticoids are widely used for inhalation therapy in asthma, for topical application to the skin in nearly all cases of dermatosis and for injection in joints, bursae, tendons, etc., as well as for topical anti-inflammatory treatment of the eye, ear and nose. The most important side effects following topical use are skin and mucosal atrophy and acne, as well as microbial superinfections. In the eye, corneal ulceration, glaucoma and viral superinfections are feared and serious side effects, and steroids are in fact contraindicated in many cases.
Other anti-inflammatory drugs include penicillamine, chloroquine, gold salts and cytostatics. The main indication for these drugs is severe rheumatoid arthritis. The drugs are all given systemically, and they all exert a number of severe side effects.
Thus there would seem to be a need for alternative drugs to be used both topically and systemically to suppress or modify inflammatory reactions.
Sulphated saccharides, primarily sucralfate, have previously been indicated for the treatment of gastric and duodenal ulcers (cf. U.S. Pat. No. 3,432,489; EP 161816; EP 192640) and for the treatment of emesis and diarrhoea in dogs and cats (cf. EP 133880). In radio-labelled form, sucralfate has also been used as a diagnostic agent for the imaging of gastrointestinal mucosa, since the substance binds selectively to ulcerated areas in the stomach and upper small intestine (cf. EP 107209).
The American Journal of Gastroenterology, 80(3), 1985, pp. 206-209; "Sucralfate: New Aspects in Therapy of Ulcers and Lesions" and the Second International Sucralfate Symposium Together With the World Congress of Gastroenterology in Stockholm, suggest the use of sucralfate for a variety of non-ulcer applications, including the treatment of stomatitis, post-sclerotic ulcer, reflux oesophagitis and bile reflux oesophagitis as well as for counteracting the ulcerogenic effects of aspirin.